PROJECT SUMMARY Acute kidney injury and chronic kidney disease are major US and global health problems and represent a sig- nificant contributor to all cause morbidity and mortality. These two disease states are interconnected and inter- dependent, the downstream effect of which is the alarming rise in chronic kidney disease worldwide. At the heart of these disease states is the response to injury and dysregulated wound repair leading to fibrosis and loss of organ function. Currently, there are no therapies for these two diseases due to our incomplete knowledge of how to uncouple the maladaptive responses. Scarless wound repair with regeneration is the ho- ly grail of wound healing, and thought to be restricted to amphibians and lower vertebrates. However, all mammalian species exhibit scar-free wound repair as embryos that is lost after birth and instead exhibit scar formation, tissue fibrosis, and loss of organ function. However, the ?Old World? clade of muroid rodents of the genus Acomys (common name-African Spiny Mouse) evolved a different course of wound repair in their native habitat of northern Africa and the Middle East. Acomys can shed up to 60% of its skin to avoid predators and then amazingly regenerate their skin without fibrosis or scarring. Acomys represent the highest vertebrate class known to exhibit tissue regeneration without scar formation as adults. In this proposal, our objective is to determine if this remarkable course of wound repair extends into the kidney. Our preliminary data suggests that evolutionary-derived genomic adaptations in Acomys lead to scarless regenerative wound repair in re- sponse to acute and chronic kidney injury. We will validate this observation using complementary strategies in vitro and in vivo and begin to define the pathways that unlock the regenerative potential of Acomys during kid- ney injury. The results of our proposed studies have the potential to transform current research and reveal tru- ly novel insights with exciting possibilities for discovery not only in kidney fibrosis but other organs as well.